Pozo-Navas Beatriz, Stessel Heike, Wölkart Gerald, Brunner Friedrich
Department of Pharmacology and Toxicology, Universität Graz, Universitätsplatz 2, A-8010 Graz, Austria.
J Pharmacol Exp Ther. 2006 Nov;319(2):729-38. doi: 10.1124/jpet.106.107854. Epub 2006 Jul 20.
We investigated the role of nitric oxide (NO) in myocardial ischemia-reperfusion injury of diabetic mice with myocyte-specific overexpression of endothelial NO synthase (NOS). Four weeks after diabetes induction with streptozotocin (blood glucose approximately 29 mM), isolated isovolumic heart function and cellular NO metabolites in response to brief normothermic ischemia-reperfusion were determined. Under normoxic conditions transgenic (TG) hearts from nondiabetic and diabetic animals generated less left-ventricular developed pressure compared with wild-type (WT) control hearts, and this abnormality was unaffected by NOS inhibition. During ischemia, the rise in end-diastolic pressure was less in the TG than WT group of nondiabetic hearts, whereas the transgene had no effect in the diabetic group. Similarly, the transgene also improved reperfusion systolic and diastolic function in nondiabetic but not in diabetic hearts. NOS inhibition worsened reperfusion function in diabetic hearts. Postischemic nitrite and cGMP formation were higher in nondiabetic TG than WT hearts, but in diabetic hearts cGMP was no longer elevated. The formation of reactive oxygen species (superoxide and peroxynitrite) during early reperfusion, measured by electron spin resonance spectroscopy, was similar in nondiabetic WT and TG hearts, but it was significantly higher in diabetic TG hearts. Stimulating endogenous NO production with 10 microM bradykinin more strongly reduced myocardial O(2) consumption in diabetic TG than diabetic WT hearts perfused in normoxia, whereas there was no difference after ischemia-reperfusion. Thus, providing additional endogenous NO is sufficient to protect nondiabetic hearts against ischemia-induced injury, but for a similar protection in diabetic hearts, effective scavenging of reactive oxygen species is also important.
我们研究了一氧化氮（NO）在心肌特异性过表达内皮型一氧化氮合酶（NOS）的糖尿病小鼠心肌缺血再灌注损伤中的作用。用链脲佐菌素诱导糖尿病4周后（血糖约29 mM），测定了离体等容心脏功能以及对短暂常温缺血再灌注的细胞NO代谢产物。在常氧条件下，非糖尿病和糖尿病动物的转基因（TG）心脏与野生型（WT）对照心脏相比，产生的左心室舒张末压较低，且这种异常不受NOS抑制的影响。在缺血期间，非糖尿病心脏的TG组舒张末压升高幅度小于WT组，而转基因对糖尿病组无影响。同样，转基因也改善了非糖尿病心脏的再灌注收缩和舒张功能，但对糖尿病心脏无效。NOS抑制使糖尿病心脏的再灌注功能恶化。缺血后，非糖尿病TG心脏中的亚硝酸盐和cGMP生成高于WT心脏，但在糖尿病心脏中cGMP不再升高。通过电子自旋共振光谱法测量，早期再灌注期间活性氧（超氧化物和过氧亚硝酸盐）的生成在非糖尿病WT和TG心脏中相似，但在糖尿病TG心脏中显著更高。在常氧灌注的情况下，用10 μM缓激肽刺激内源性NO生成，糖尿病TG心脏比糖尿病WT心脏更能强烈降低心肌耗氧量，而在缺血再灌注后则无差异。因此，提供额外的内源性NO足以保护非糖尿病心脏免受缺血诱导的损伤，但对于糖尿病心脏的类似保护，有效清除活性氧也很重要。
